Benzene-sulfonyl semicarbazides and process for preparing them

ABSTRACT

BENZENE-SULFONYL SEMICARBAZIDES HAVING HYPOGLYCEMIC PROPERTIES AND CORRESPONDING TO THE GENERAL FORMULA   1-(R-CO-NH-Y-),4-(R1-NH-CO-NH-SO2-)BENZENE   WHEREIN R (A) REPRESENTS PHENYL WHICH MAY BE SUBSTITUTED ONCE OR TWICE BY SUBSTITUENTS OF THE GROUP LOWER ALKYL, ALKENYL, ALKOXY, ALKENOXY, ALKOXYALKOXY, ACYL, HALOGEN, OR TRIFLUOROMETHYL, OR BY THE METHYLENE-DIOXY GROUP, (B) THIENYL WHICH MAY BE SUBSTITUTED ONCE OR TWICE BY SUBSTITUENTS OF THE GROUP HALOGEN, LOWER ALKYL, ALKOXY, ALKENYLOXY, ALKOXYALKOXY, PHENALKOXY OR ARYL, OR BY A POLYMETHYLENE CHAIN LINKED AT ITS TWO ENDS TO THE THIENYL GROUP, WHICH CHAIN CONTAINS FROM 3 TO 4 CARBON ATOMS, Y REPRESENTS-CH2-CH2-,-CH2-CH-(CH3)-OR -CH(CH3)-CH2-, R1 REPRESENTS (A) A B,B-ENDOETHYLENE-HEXAMETHYLENE IMINE OR A CORRESPONDING CYCLIC SYSTEM HAVING A C=C DOUBLE LINKAGE, (B) A HEXAHYDRO-ISO-INDOLINE, A TETRAHYDRO-ISO-INDOLINE, A 4,7-ENDOALKYLENE-HEXAHYDRO-ISO-INDOLINE OR A 4,7-ENDOALKYLENE-TETRAHYDRO-ISO-INDOLINE, HAVING 1 TO 2 CARBON ATOMS IN THE ENDOALKYLENE GROUP IN THE CASE OF TETRAHYDRO-COMPOUNDS THE DOUBLE LINKAGE BEING IN 5,6-POSITION, (C) AN ISO-INDOLINE, AN INDOLINE, A HEXAHYDRO-INDOLINE, A TETRA- OR DECAHYDRO-QUINOLINE; A TETRA- OR DECAHYDRO-ISO-QUINOLINE, (D) AN N-3-AZASPIRO-(5,5)-UNDECANE, (E) AN N-THIOMORPHOLINE, (F) THE FOLLOWING GROUPS   HEXAHYDRO-4,7(1&#39;&#39;,2&#39;&#39;)CYCLOPROPANOISOINDOLIN-2-YL   3A,4,7,7A-TETRAHYDRO-4,7(1&#39;&#39;,2&#39;&#39;)CYCLOPROPANOISOINDOLIN-2-YL   HEXAHYDRO-4,7(1&#39;&#39;,2&#39;&#39;)CYCLOBUTANOISOINDOLIN-2-YL   3A,4,7,7A-TETRAHYDRO-4,7(3&#39;&#39;,4&#39;&#39;)-1-CYCLOBUTENO   ISOINDOLIN-2-YL   AND SALTS THEREOF.

United States Patent Int. Cl. C07d 41/04 US. Cl. 260239 BA 6 ClaimsABSTRACT OF THE DISCLOSURE Benzene-sulfonyl semicarbazides havinghypoglycemic properties and corresponding to the general formula whereinR (a) represents phenyl which may be substituted once or twice bysubstituents of the group lower alkyl, alkenyl, alkoxy, alkenoxy,alkoxyalkoxy, acyl, halogen, or trifluoromethyl, or by themethylene-dioxy group, (b) thienyl which may be substituted once ortwice by substituents of the group halogen, lower alkyl, alkoxy,alkenyloxy, alkoxyalkoxy, phenalkoxy or aryl, or by a polymethylenechain linked at its two ends to the thienyl group, which chain containsfrom 3 to 4 carbon atoms,

R represents (a) a 3,fl-endoethylene-hexamethylene imine or acorresponding cyclic system having a C -C double linkage,

(b) a hexahydro-iso-indoline, a tetrahydro-iso-indoline, a4,7-endoalkylene-hexahydro-iso-indoline or a4,7-endoalkylene-tetrahydro-iso-indoline, having 1 to 2 carbon atoms inthe endoalkylene group, in the case of tetrahydro-compounds the doublelinkage being in 5,6-position,

(c) an iso-indoline, an indoline, a hexahydro-indoline, a tetraordecahydro-quinoline; a tetraor decahydro-iso-quinoline,

(d) an N-3-azaspiro-[5,51-undecane,

(e) an N-thiomorpholine,

(f) the following groups and salts thereof.

The present invention provides benzene-sulfonyl semicarbazides of theformula and definition set forth in the abstract. The new semicarbazidesand their salts are valuable medicinal agents distinguished by a strongand particularly long-lasting blood-sugar lowering activity.

The term lower always characterizes groups or radicals having 1 to 4carbon atoms. There are especially preferable compounds wherein Rrepresents a phenyl group substituted in 2-position by lower alkoxyoralkenoxy and in 4- or S-position by a halogen atom or by a lower alkylor alkoxy.

The present invention further relates to a process for 3,705,151Patented Dec. 5,, 1972 ICC preparing said benzenesulfonylsemicarbazides. As methods for preparation, there may be mentioned thefollowing methods:

(21) Reaction of RCONHY-substituted benzenesulfonamides, preferably inthe form of their salts, with imino-carbamic acid esters,imino-thiocarbamic acid esters, or imino-ureas containing as iminoradical the group R (b) reaction of hydrazines of the formula R NH ortheir salts with RCONHY-substituted benzenesulfonyl isocyanates,benzenesulfonyl carbamic acid esters, benzenesulfonyl thiocarbamic acidesters, carbamic acid halides or ureas,

(c) reaction of RCONHY-substituted benzenesulfo-chlorides with R-substituted ureas or preferably with their salts,

(d) hydrolysis of benzenesulfonyl-isosernicarbazide ethers,

isothiosemicarbazide ethers or benzenesulfonyl-iminoparabanic acids,

(e) exchange of the sulfur atom for an oxygen atom, in benzenesulfonylthiosemicarbazides of the formula (f) introduction of the radical RCO,if desired in one or several steps, into benzenesulfonyl semicarbazidesof the formula by acylation.

The benzenesulfonyl semicarbazides obtained may then be converted, ifdesired, into their salts by treatment with alkaline agents or withphysiologically tolerable inorganic or organic acids.

As semicarbazides or imino-ureas for the syntheses mentioned under (a),there are suitable compounds of the formula R NH CO--NH or acylatedcompounds of the formula R NHCO-NH-acyl, wherein acyl represents analiphatic or aromatic acid radical, preferably of lower molecularweight, or diphenyl semicarbazides of the formula R --NH- CO-N(C Hwherein the phenyl radicals may be substituted or may be linked to eachother directly or by means of a bridge member such as -CH NH, O- or S-,or N,N- disubstituted carbohydrazides of the formula Especially suitableas benzenesulfonyl carbamic acid halides are the chlorides.

Furthermore, corresponding benzenesulfonyl ureas which may beunsubstituted at the terminal nitrogen atom, or substituted once ortwice by alkyl or aryl groups, may be converted into the final productsby reacting these with hydrazines of the formula R NH if desired, in theform of their salts. Instead of the benzenesulfonyl ureas substituted inthis manner, there may be used the correspondingN-benzenesulfonyl-N-acyl ureas, benzene-sulfonyl-carbamoyl-imidazols,benzenesulfonyl-carbamoylpyrazols or benzene-sulfonyl-carbamoyl-triazolsor bis- (benzenesulfonyD-ureas which carry at one of the nitrogen atomsanother substituent, for example methyl. Such bisbenzenesulfonyD-ureasor N-'benzene-sulfonyl-Nacylureas may be treated with hydrazines of theformula R NH and the salts obtained may be heated to elevatedtemperatures, preferably to at least C.

The imino-carbamic acid esters or benzenesulfonyl carbamic acid estersmentioned, as well as the corresponding thioesters, contain in the estercomponent preferably an alkyl radical of low molecular weight or aphenyl radical.

The benzenesulfonyl isosemicarbazide ethers, -isothiosemicarbazideethers or -parabanic acids, used as starting materials, may be obtainedby reacting corresponding isosemicarbazide ethers, isothiosemicarbazideethers or parabanic acids with corresponding benzenesulfochlorides.Benzenesulfonyl isosemicarbazide ethers are also obtained, in the firstplace, by desulfurizing benzenesulfonyl thiosemicarbazides in methanol.They are subsequently converted into benzenesulfonyl semicarbazides byhydrolysis.

Depending on the nature of the member RCO--, in some cases, the one orthe other of the previously described methods may prove unsuitable forpreparing the individual compounds falling under the general formula, orat least will make it necessary for active groups to be protected. Suchrelatively rare cases can easily be recognized by the expert, and thereis no difficulty in successfully applying another one of the synthesesdescribed.

As regards the reaction conditions, the process embodiments of thepresent invention may in general, vary within wide limits and may beadapted to each individual case. [For example, the reactions can beefiected with the use of solvents, at room temperature or at an elevatedtemperature.

As starting substances there are used, as one reactant, compoundscontaining a benzene radical substituted by the group RCO-NHY---. Asradical R may be mentioned, for example, the following groups:

@- 3 1 F: F Ha The sulfonyl-semicarbazide derivatives obtainableaccording to the present invention, are valuable medicinal agents whichare distinguished by a strong action of lowering the blood sugar level.This applies, in particular,

to such compounds in which R represents a phenyl radical 75 l I 01 OH aTABLE Lowering of the blood sugar level in rabbits after ad- Limitamount ministering 10 causing lowermgJkg. per os ing of the after bloodsugar level in 3 hours, 24 hours, rabbits, Compound percent percentmg./kg.

N-[4-(6- 2-methoxy-5-chlorobenzamido-ethyl)-benzenesullonyH-l,1-(2,5-endoethylenehexarnethylene)-semicarbazide 36 31 0. 1 4-[4-(a-2-rneth0xy-5-methylbenzamido -ethyl) -b enzenesulfonyH-l,1-(2,5endoethylene hexamethylene)-semicarbazide 14 24 0. 06

I CHaO I SE3 2 CH3 In contradistinction thereto, the[N-(4methylbenzenesulfonyl)-N-n-butyl-urea] known as antidiabetic andused as medicinal agent shows no lowering of the blood sugar level whenadministered in a dose of 25 mg./kg. in a comparative test.

The toxicities of the products of the invention are very low, they arewithin the range of the above-mentioned N-(4-methy1benzenesulfonyl)-N'-n-butyl-urea which is very well tolerable.

It is preferable to process the products of the present invention intoorally administerable preparations which have blood sugar loweringaction and which can accordingly be used in the treatment of diabetesmellitus; these can be employed as such or in the form of their salts orin the presence of substances causing salt formation. For such saltformation there can be used, for example, alkaline agents such as alkalimetal hydroxides, alkaline earth metal hydroxides, alkali metalcarbonates, alkaline earth metal carbonates, alkali metal bicarbonatesand alkaline earth metal bicarbonates or physiologically toleratedacids. The pharmaceutical preparations are preferably in the form oftablets which contain, in addition to the compounds of the presentinvention, the usual adjuvants and carriers such as talc, starch,lactose, tragacanth, magnesium stearate and the like.

The following examples serve to illustrate the present invention, butthese are not intended to limit it thereto:

EXAMPLE 1 4 [4 (B 2-methoXy-5-chlorobenzamino -ethyl)- benzenesulfonyl]1,1 (2,5-endoethylene-hexamethylene)-semicarbazide 4.2 grams of N [4 (B-2-methoxy-5-chlorobenzamido ethyl) benzenesulfonyl] methyl-urethane(melting point l89l9l C.) were suspended in 75 milliliters of dioxaneand 1.6 grams of 1,1-(2,5-endoethylenehexamethylene)-hydrazine wereadded thereto. The mixture was heated to 110 C. for 1 hour, aftercooling it was precipitated by adding water and the 4-[4-(B- 2- methoxy5 chlorobenzamido ethyl) benzenesulfonyl] 1,1 (2,5 endoethylenehexamethylene) semicarbazide obtained was purified by reprecipitating itwith dilute ammonia/glacial acetic acid and recrystallization frommethanol (melting point 173-175" C.).

In an analogous manner there were obtained:

from N [4 (B 3 trifluoromethyl benzamido ethyl) benzenesulfonyl]methylurethane (melting point 178180 C.) 4 [4 (B3-trifiuoromethylbenzamido ethyl) benzenesulfonyl] l.l (2.5-endoethylene hexamethylene) semicarbazide of the melting point 193-195C. (from methanol);

from N [4 (B 3 chlorobenzamido ethyl)- benzenesulfonyl] methyl urethane(melting point 173-175" C.) 4 [4 (B 3 chlorobenzamido ethyl)benzenesulfonyl] 1.1 (2.5 endoethylenehexamethylene) semicarbazide ofthe melting point l98-200 C. (from methanol/dimethylfo-ramide);

from N [4 (B 3 methoxythiophene 2 carbonamido ethyl) benzenesulfonyl]methylurethane (melting point 226-228 C.) 4 [4 (B- 3- methoxythiophene 2carbonamido ethyl) benzenesulfonyl] 1.1 (2.5 endoethylenehexamethylene)semicarbazide, melting point 166168 C. (from methanol);

from N [4 (B 3.4 dichlorobenzamido ethyl)- benzenesulfonyl]methylurethane (melting point 198 200 C.) 4 [4 (B 3.4 dichlorobenzamidoethyl) benzenesulfonyl] 1.1 (2.5 endoethylenehexamethylene)semicarbazide, melting point 178- 180 C. (frommethanol/dimethylformamide);

from N [4 (B 3.5 dimethylthiophene 2 carbonamido ethyl) benzenesulfonyl]methylurethane (melting point 170-172 C.) 4 [4 (B 3.5- dimethylthiophene2 carbonamido ethyl) benzenesulfonyl] 1.1 (2.5 endoethylenehexamethylene) semicarbazide, melting point 184-186 C. (from methanol);

from N [4 (B 2 methoxybenzamido ethyl)- benzenesulfonyl] methylurethane(melting point 174- 176 C.) 4 [4 (B 2 methoxybenzamido ethyl)benzenesulfonyl] 1.1 (2.5 endoethylenehexamethylene) semicarbazide,melting point 152 C. (from methanol);

from N [4 (B 2 methoxy 5-methyl-benzamidoethyl) benzene sulfonyl]methylurethane (melting point l75-l77 C.) 4 [4 (B 2 methoxy-S-methylbenzamido ethyl) benzenesulfonyl] 1.1- (2.5 endoethylenehexamethylene) semicarbazide, melting point l66l68 C. (from methanol);

from N [4 (B 2 methoxy 5 bromo benzamido ethyl) benzenesulfonyl]methylurethane (melting point l97-l99 C.) 4-[4-(B- 2-methoXy-5-bromobenzamido ethyl) -benzenesulfonyl] 1 l- 2.5 endoethylenehexamethylene) semicarbazide, melting point l85l87 C. (from methanol);

from N [4 (B 2 ethoxy 5 chlorobenzamido ethyl) benzenesulfonyl]methylurethane (melting point 203205 C.) 4 [4 (B 2ethoxy-S-chlorobenzamido ethyl) benzenesulfonyl] 1.1 (2.5- endoethylenehexamethylene) semicarbazide, melting point 196-l98 C. (frommethano/dimethylformamide);

from N [4 (B 3.5 dimethylbenzamido ethyl)- benzenesulfonyl]methylurethane (melting point 223- 225 C.) 4 [4 (B 3.5 dimethylbenzamidoethyl) benzenesulfonyl] 1.1 (2.5 endoethylenehexamethylene)semicarbazide, melting point 211- 213 C. (frommethanol/dimethylformamide);

from N [4 (B 2 ethoxy 5 fluorobenzamido ethyl) benzenesulfonyl]methylurethane (melting point l93-195 C.) 4 [4 (B 2 ethoxy 5fluorobenzamido ethyl) benzenesulfonyl] l.l (2.5- endoethylenehexamethylene) semicarbazide, melting point l6l-163 C. (from methanol);

from N [4 (B 2 ethoxy 5 acetylbenzamido ethyl) benzenesulfonyl]methylurethane (melting point l64-l66 C.) 4 [4 (B 2ethoxy-S-acetylbenzamido ethyl) benzenesulfonyl] 1.1 (2.5- endoethylenehexamethylene) semicarbazide, melting point l96l98 C. (from methanol);

from N [4 (B 3 chlorobenzamido ethyl)- benzenesulfonyl] methylurethane(melting point 173- 175 C.) N [4 (B 3 chlorobenzamido ethyl)-benzenesulfonyl] N (decahydro quinolino)-urea, melting point 245-247 C.(decomposition) (from methanol/dimethylformamide) from N [4 (B 3ethoxythiophene 2 carbonamido ethyl) benzenesulfonyl] methylurethane(melting point 163-l65 C.) N [4 (B 3 ethoxythiophene 2 carbonamidoethyl) benzenesulfonyl] N decahydroquinolino urea, melting point186-187" C. (form methanol/dimethylformamide);

from N [4 (B 2 methoxybenzamido ethyl)- benzenesulfonyl] methylurethane(melting point 174- 176 C.) N [4 (B 2 methoxybenzamido ethyl)benzenesulfonyl] N decahydroquinolinourea, melting point 205206 C. (frommethanol/ dimethylformamide) from N [4 (B 2 methoxy 5 chlorobenzamidoethyl) benzenesulfonyl] methylurethane (melting point l93l94 C.) N [4 (B2 methoXy 5- chlorobenzamido ethyl) benzenesulfonyl] N-decahydroquinolino urea, melting point 2l82l9 C. (frommethanol/dimethylformamide) and N [4 (B- 2 methoxy 5 chlorobenzamidoethyl) benzenesulfonyl] N tetrahydroisoquinoline urea, melting point148l50 C. (from methanol);

from N [4 (B 2 methoxy 5 methylbenzamido ethyl) benzenesulfonyl]methylurethane (melting point l75l77 C.) N [4 (B 2 methoxy-5methylbenzamido ethyl) benzenesulfonyl] N'- decahydroquinolino-urea,melting point 200-202 C. (from methanol/dimethylformamide) and N [4 (B-2 methoxy 5 methylbenzamido ethyl) benzenesulfonyl] Ntetrahydroisoquinolino-urea, melting point l82l84 C. (frommethanol/dimethylformamide);

from N [4 ([3 3 methoxy 5 chlorothiophene-Z- carbonamido ethyl)benzenesulfonyl] methylurethane (melting point 186188 C.) N [4 (/3- 3-methoxy 5 chlorothiophene 2 carbonarnido ethyl) benzenesulfonyl] Ntetrahydroisoquinolinourea, melting point 177179 C. (from methanol/dimethylformamide) from N [4 (,8 2 methoxy 4 trifluoromethylbenzamidoethyl) benzenesulfonyl] methylurethane (melting point 190192 C.) N [4 82- methoxy 4 trifluormethylbenzamido ethyl)- benzenesulfonyl] 1.1 (2.5endoethylene hexamethylene) semicarbazide, melting point 172l74 C. (frommethanol);

fromN [4 (B 2 methoxy benzamido ethyl)- benzenesulfonyl] ethylurethane(melting point 144 C.) N [4 ([3 2 methoxy benzamido -ethyl)-benzeuesulfonyl] N (3 azaspiro [5,5] undecyl- 3) urea (melting point187l88 C.);

from N [4 (B 2 methoxy 5 chlorobenzamido ethyl) benzenesulfonyl]methylurethane (melting point 178179 C.) N [4 (fl 2- methoxy 5 chlorobenzamido ethyl)-benzenesulfonyl] N (3 azaspiro [5,5] undecyl-3)-ureamelting point 166-169 C.) and N [4 (B 2- methoxy 5 chloro benzamidoethyl) benzenesulfonyl] N (N thiomorpholyl) urea (melting point 194196C.);

from N [4 (B 2 methoxy-5-methyl-benzamido ethyl) benzenesulfonyl]ethylurethane (melting point 166l70 C.) N [4 (,6 2 methoxy 5methylbenzamido ethyl) benzenesulfonyl] N 3-azaspiro [5,5] undecyl 3)urea (melting point 171- 173 C.);

from N [4 (5 2 methoxy 5 fluoro-benzamido ethyl) benzenesulfonyl]ethylurethane (melting point 123 C.) N [4 ([3 2 methoxy 5fluorobenzamido ethyl) benzenesulfonyl] N (3- azaspiro [5,5] undecyl 3)urea (melting point 173 (3.);

from N [4 (5 benzamido ethyl) benzenesulfonyl1- methylurethane (meltingpoint 186 C.) N [4 (B- benzamido ethyl) benzenesulfonyl] N (3-azaspiro[5,5] undecyl 3) urea (melting point 186- 187 C.);

from N [4 ([3 3 chloro benzamido ethyl)- benzenesulfonyl] methylurethane(melting point 174- 176 C.) N [4 (,8 3 chloro benzamido ethyl)benzenesulfonyl] -N'- 3-azaspiro- [5 ,5 -undecyl- 3) urea (melting point183184 C.).

EXAMPLE 2 N [4 (B- 2-methoxy-5-chlorobenzamido ethyl)-benzenesulfonyl] N(4,7 methano hexahydro-isoindolino2)-urea 12.8 grams ofN-[4-(,8-2-methoXy-5-chlorobenzamidoethyl) benzenesulfonyl] methylurethane were dissolved in 150 milliliters of dioxane. While stirring4.6 grams of N aInino-4,7-methano-hexahydro-iso-indoline were addedthereto and the whole was heated to 100 C. for 1.5 hours while stirringwas continued. After dioxane had been distilled off in vacuo, theresidue was dissolved in dilute ammonia (1:25), filtered and acidifiedwith dilute acetic acid. The N-[4-(p- 2-methoxy-5-chlorobenzamido ethyl)benzenesulfonyl] N (4,7- methano hexahydro iso indolino 2) urea thusobtained melted at 163165 C. after recrystallization from dilutemethanol/dioxane.

In an analogous manner there were obtained from the correspondingsulfonyl-urethane (1) N [4 (p benzamido ethyl) benzenesulfonyH- N (4,7methano hexahydro isoindolino 2)- urea, melting point '-19-2 C. (fromdilute methanol/dioxane);

(2) N [4 (5 4 chloro-benzamido -ethyl)-benzenesulfonyl] N (4,7 methanohexahydro-isoindolino 2) urea, melting point 203.5-205.5 C. (from dilutemethanol/dioxane);

(3) N [4 (,8 thiophene 2 carbonamido ethyl)- benzenesulfonyl] N (4,7methano hexahydroisoindolino 2) urea, melting point 229-231 C. (fromdilute methanol/dioxane);

(4) N [4 (,8 5 chloro thiophene 2 carbonamido ethyl) benzenesulfonyl] N(4,7- endomethylene hexahydro isoindolino 2) urea, melting point 173-175C.;

(5) N [4 (B benzamido ethyl) benzenesulfonyl1- N (3,6 endoethylenehexamethylene imino)- urea, melting point 191193 C.

We claim: 1. A benzene-sulfonyl semicarbazide of the formula wherein Rrepresents (a) phenyl which may carry one or two substituents selectedfrom the group, consisting of lower alkyl, lower alkoxy, lower alkanoyl,halogen, or trifiuoromethyl,

(b) thienyl which may carry one or two substituents selected from thegroup consisting of halogen, lower alkyl, or lower alkoxy,

Y represents -CH CH -CH -CH--(CH or -CH(CH )--CH and R representsB,fl-endoethylene-hexamethylene-imine.

2. A benZene-sulfonyl semicarbazide as claimed in claim 1, wherein Rrepresents phenyl substituted in 2- position by lower alkoxy.

3. A benzene-sulfonyl semicarbazide as claimed in claim 1, wherein Rrepresents phenyl substituted in 2- position by lower alkoxy and in 4-or 5-position by halogen, lower alkyl or lower alkoxy.

4. A benzene-sulfonyl semicarbazide as claimed in claim 1, wherein Rrepresents phenyl substituted in 2- position by methoxy and in 4- or5-position by halogen, methyl or methoxy.

5. A benzene-sulfonyl semicarbazide as claimed in claim 1, wherein Rrepresents phenyl substituted in 2- position by methoxy and in5-position by halogen or methyl.

6. N [4 (,8 2 methoxy 5 chlorobenzamido ethyl) benzene sulfonyl] 1,1(2,5 endoethylenehexamethylene) -semicarbazide.

References Cited UNITED STATES PATENTS 3,432,491 3/1969 Jucker et a1260239.6

ALEX MAZEL, Primary Examiner R. V. RUSH, Assistant Examiner US. Cl. X.R.

260-243 B, 293.56, 287 R, 326.1, 326.11, 332.2 C; 424-246, 258, 267,274, 275

